PROJECT SUMMARY This objective of this proposal is to examine the specific role of the anti-inflammatory and pro-resolving protein Annexin A1 (AnxA1) during the development and onset of Sjgren's Syndrome (SjS), the second most common rheumatic disease that primarily targets the salivary and lacrimal glands causing clinical dry eye and dry mouth symptoms. Pathophysiological events in SjS are strongly associated with aberrant proteolysis. The proposal hypothesizes that SjS-associated proteolytic processing alter the anti-inflammatory and pro-resolution properties of AnxA1. While loss of AnxA1 has been associated with uncontrolled proliferation and activation of autoreactive Th17 cells in the mouse model of experimental autoimmune uveitis, there is a critical knowledge gap about AnxA1 in the SjS disease process. In our preliminary studies, we discovered cleavage products of the N-terminal region of AnxA1 that harbors the main pharmacophore for the anti-inflammatory properties of AnxA1. Aim 1 will determine whether preventive treatment with N-terminal AnxA1 peptide ac2-26 will reduce inflammation, modulate T cell response and prevent salivary gland destruction in the NOD mouse model. Aim 2 will evaluate the effect of AnxA1-protective protease inhibitors on the development and onset of SjS in NOD mice. Results from this study will provide critical insights into the role of AnxA1 in modulating autoimmune response and promote resolution in SjS and suggest novel mechanism-derived strategies for diagnosis and controlling inflammation and tissue dysfunction and destruction in SjS.